Funding is requested towards the purchase of a Waters nanoACQUITY Ultra Performance LC and Thermo Fisher Scientific nano-electrospray ionization Linear Quadrupole Ion Trap - Orbitrap (LTQ-Orbitrap) Velos mass spectrometer system which would provide a uniquely high performance mass spectrometer for the MS &Proteomics Resource within the Keck Laboratory at Yale University. The LTQ-Orbitrap Velos is one of the newest Orbitrap MS platforms in its class that has sub-parts-per-million mass accuracy, a new atmospheric pressure interface lens design, and other high pressure ion trapping and ion transmission characteristics that together make the new Velos platform 2 times faster and 5-10 times more sensitive than its Model XL predecessor. Currently, Yale University has one LTQ-Orbitrap XL that is available on a service charge basis and that is located within the MS &Proteomics Resource of the Keck Laboratory. This Resource annually provides proteomics technologies to about 100 Yale and 110 non-Yale investigators at 90 institutions. The demand for technologies supported by its LTQ-Orbitrap XL has increased so rapidly that the delay for SILAC, Label-Free Quantitation, phosphoproteomics, and many other technologies dependent upon the LTQ-Orbitrap Velos has now reached >75 days with this instrument being run continuously at maximum capacity. Addition of the requested LTQ-Orbitrap Velos to this Resource would greatly reduce the sample backlog and provide a 5- 10 fold increase in sensitivity that would enable investigators to reach deeper into the human and other complex proteomes than is currently possible. The higher speed of the LTQ-Orbitrap Velos would enable more peptides to be identified and quantified from each protein in a SILAC or other experiment which would provide more positive protein identifications and also would increase the statistical significance of observed differences in protein expression. Advances incorporated into the LTQ-Orbitrap Velos also make it an ideal platform to support the phosphoproteomics technologies that have become a hallmark of this Resource. This application is supported by 49 major users/investigators at Yale and 8 other institutions including Mt. Sinai School of Medicine, Rockefeller U., the U. of Chicago, and Stanford U. who propose to carry out 51 research projects that depend upon the requested instrumentation. The proposed major users of the requested instrumentation include members of four NIH Centers that are closely associated with the Keck Laboratory and that have strong proteomics components (i.e. Yale/NIDA Neuroproteomics Center, the Proteomics Shared Resource in the NCI-funded Yale Cancer Center, the Proteomics Core of the NIAID-funded Northeast Center of Excellence for Biodefense, and the Yale/NHLBI Proteomics Center which has a pending competitive renewal). The strengths of this proposal are manifold and include very strong institutional support;the 30 year record of achievement of the Keck Laboratory, which is one of the oldest and largest biotechnology core labs in academia;and the 50 very highly trained and uncommonly dedicated staff that are the Keck Laboratory.